August 15, 2002
New Findings Change Understanding of Adult Stem Cells
Researchers have found neural stem cells in the peripheral nervous
system of adult animals, where they were not believed to exist. The
studies show that the intrinsic properties of neural stem cells vary
according to the region of the peripheral nervous system in which the
cells are located.
Taken together, these findings, which were published in two articles
in the August 15, 2002, issue of the journal Neuron, suggest
that successful application of stem cells to regenerate damaged
peripheral nervous system (PNS) tissue will require that researchers
match the origin of the stem cell to the specific tissue they are
trying to repair.
Stem cells are immature progenitor cells that give rise to more
specialized cells that form tissues and organs. Neural stem cells give
rise to the nervous system. “Although great progress has been
made in understanding the properties of stem cells, we are just
beginning to understand how those functions are regulated,” said
Howard Hughes Medical Institute investigator Sean J. Morrison, who is
at the University of Michigan.
Morrison and his colleagues have been studying stem cell biology in
the context of neural development and blood cell development. The
studies published in Neuron focused on neural crest stem cells
(NCSCs), which were so-named because during embryonic development, they
migrate out of the neural tube and give rise to a number of different
tissues including the peripheral nervous system.
Morrison and his colleagues decided to search for NCSCs in adult
animals because their studies of rat embryos were revealing that the
cells were present much later in development than they thought
possible. The idea that these cells would be found in the peripheral
nervous system ran counter to prevailing opinions, said Morrison.
"Previous work on the peripheral nervous system suggested that
neural crest stem cells differentiated during fetal development," he
said. "People firmly believed that there would be no neural crest stem
cells in the adult peripheral nervous system. It had been known for
quite a while, however, that there are stem cells in the adult central
nervous system. But the CNS was thought to be a more dynamic
environment where stem cells and neurogenesis could persist throughout
adult life, at least in certain locations.”
Forging ahead, Morrison’s group isolated NCSCs from the gut
tissue of adult rats, cultured those cells and then introduced them
into chick nerves to explore properties of the NCSCs. These studies
showed that the NCSCs were self-renewing and multipotent, meaning they
were able to differentiate into both neurons and supporting glial
cells. These adult cells had most of the properties of embryonic NCSCs,
but they were unable to become serotonergic and noradrenergic neurons,
two cell types that embryonic NCSCs are capable of becoming.
"This finding was significant because some people assumed that adult
stem cells would have the same properties as fetal stem cells," said
Morrison. "But work on blood-forming stem cells suggested just the
opposite — that while the adult stem cells are self-renewing and
multipotent, they do change their properties in certain ways. They lose
the ability to make certain subtypes of cells that are made only during
fetal development. And in the PNS, serotonergic neurons and
noradrenergic neurons are only made during fetal development,
suggesting that NCSCs undergo changes perinatally that are analogous to
those in blood-forming stem cells."
According to Morrison, much work remains to fully understand adult
stem cells and whether they might one day have clinical applications.
"We don't know yet whether these cells exist in humans," he said. "And
we don’t know what they normally do in the gut. But these findings
offer the possibility that there could be stem cells that can engage in
repair of the PNS, without requiring exogenous cells to be
transplanted. That opens up a new spectrum of therapeutic opportunities
that we didn’t even think were on the table."
In a related set of experiments, Morrison and his colleagues
isolated NCSCs from the gut and sciatic nerve of rat embryos. They then
tested how the cells from these two different tissues responded to
various regulatory signals, in an attempt to reveal whether there were
intrinsic differences in the cells.
"In the past, people have argued that distinct regions of the
nervous system were different because they were in different
environments," said Morrison. "And people have gone to the point of
arguing that there might be a single type of neural stem cell within
the CNS, as though the stem cell itself was a blank slate."
Morrison and his colleagues developed a technique that enabled them
to compare the newly isolated cells at the same point in development
and before they had been cultured. This technique allowed them to study
the cells before they were exposed to chemicals in the cell culture
that might erase the intrinsic properties of the cells.
Their studies revealed intrinsic differences in the two types of
NCSCs. Gut NCSCs were more responsive to chemical signals that caused
differentiation into neurons, and sciatic nerve NCSCs were more
responsive to signals that produced glial cells. When the researchers
transplanted the cells into developing chick nerves, the gut NCSCs made
only neurons and the sciatic nerve cells produced only glial cells.
According to Morrison, the emerging theory is that stem cells rely
on a combination of intrinsic properties and environmental signals to
develop into the diverse populations of adult cells observed in the
nervous system.
"The clinical implications of these findings could be important," he
said. "People attempting to use neural stem cells therapeutically have
tended to think that any stem cell that makes a neuron will do, and
that you only need to get the culture conditions right. But our finding
that stem cells from different regions of the peripheral nervous system
have intrinsic differences in their ability to respond to factors, and
their ability to make different types of cells, suggests that it’s
really important to match the origin of the stem cell to the
therapeutic job that you’re trying to do."
The team in the Morrison laboratory that performed these studies was
led by graduate student Genevieve Kruger and Research Assistant Suzanne
Bixby, and included graduate student Nancy Joseph and postdoctoral
fellows Jack Mosher and Toshihide Iwashita.
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